Early co-expression of cyclooxygenase-2 and renin in the rat kidney cortex contributes to the development of N(G)-nitro-L-arginine methyl ester induced hypertension.

We investigated the involvement of cyclooxygenase-2 (COX-2) and the renin-angiotensin system in N(G)-nitro-L-arginine methyl ester (L-NAME)-induced hypertension. Male Wistar rats were treated with L-NAME (75.0 mg·(kg body mass)(-1)·day(-1), in their drinking water) for different durations (1-33 days). COX-2 and renin mRNA were measured using real-time PCR in the renal cortex, and prostanoids were assessed in the renal perfusate, whereas angiotensin II (Ang II) and Ang (1-7) were quantified in plasma. In some rats, nitric oxide synthase inhibition was carried out in conjunction with oral administration of captopril (30.0 mg·kg(-1)·day(-1)) or celecoxib (1.0 mg·kg(-1)·day(-1)) for 2 or 19 days. We found a parallel increase in renocortical COX-2 and renin mRNA starting at day 2 of treatment with L-NAME, and both peaked at 19-25 days. In addition, L-NAME increased renal 6-Keto-PGF(1α) (prostacyclin (PGI2) metabolite) and plasma Ang II from day 2, but reduced plasma Ang (1-7) at day 19. Captopril prevented the increase in blood pressure, which was associated with lower plasma Ang II and increased COX-2-derived 6-Keto-PGF(1α) at day 2 and plasma Ang (1-7) at day 19. Celecoxib partially prevented the increase in blood pressure; this effect was associated with a reduction in plasma Ang II. These findings indicate that renal COX-2 expression increased in parallel with renin expression, renal PGI2 synthesis, and plasma Ang II in L-NAME-induced hypertension.

Sub-chronic copper pretreatment reduces oxidative damage in an experimental Huntington's disease model.

Quinolinic acid (QUIN) striatal injection in rat reproduces the main neurochemical features of Huntington's disease (HD), including oxidative damage. In this study, we evaluated the effect of a copper (Cu) supplement in drinking water (90 ppm Cu, 28 days) on the QUIN-induced HD model in the rat. Copper exposure caused no signs of liver toxicity; however, it produced significant Cu accumulation in striatum. It is noteworthy that QUIN also caused increased striatal Cu content; when the supplement was administered to animals with QUIN-injury, an even higher metal striatal accumulation was observed. Cu pre-treatment preserved striatal gamma-aminobutyric acid (GABA) content, which was reduced by QUIN intrastriatal injection. Similarly, apomorphine-induced circling behavior was reduced in Cu-pretreated QUIN-damaged rats. Metal supplement in drinking water prevented both lipid peroxidation and reactive oxygen species (ROS) formation caused by QUIN in striatum. In Cu-treated groups, superoxide dismutase-1 (SOD1) activity showed a significant increase, while SOD2 activity was slightly enhanced. Although the pathophysiological role for higher Cu levels in patients with HD and in experimental models of the disease is not fully understood, results in the present study suggest that Cu oral intake stimulates anti-oxidant defenses, an effect that may be a potential factor for reducing the progression of HD.

Endothelial nitric oxide synthase impairment is restored by clofibrate treatment in an animal model of hypertension.

Adequate production of nitric oxide (NO) by endothelial nitric oxide synthase (eNOS) requires eNOS coupling promoted by tetrahydrobiopterin (BH(4)). Under pathological conditions such as hypertension, BH(4) is diminished, avoiding eNOS coupling. When eNOS is "uncoupled", it yields a superoxide anion instead of NO. Peroxisome proliferator activated receptors (NR1C) are a family of nuclear receptors activated by ligand. Clofibrate, a member of a hypolipidemic class of drugs, acts by activating the alpha isoform of NR1C. To determine the participation of NR1C1 activation in BH(4) and dihydrobiopterin (BH(2)) metabolism and its implications on eNOS coupling in hypertension, we performed aortic coarctation (AoCo) at inter-renal level on male Wistar rats in order to have a hypertensive model. Rats were divided into the following groups: Sham+vehicle (Sham-V); AoCo+vehicle (AoCo-V); Sham+clofibrate (Sham-C), and AoCo+clofibrate (AoCo-C). Clofibrate (7 days) increased eNOS coupling in the AoCo-C group compared with AoCo-V. Clofibrate also recovered the BH(4):BH(2) ratio in control values and prevented the rise in superoxide anion production, lipoperoxidation, and reactive oxygen species production. In addition, clofibrate increased GTP cyclohydrolase-1 (GTPCH-1) protein expression, which is related with BH(4) recovered production. NR1C1 stimulation re-establishes eNOS coupling, apparently through recovering the BH(4):BH(2) equilibrium and diminishing oxidative stress. Both can contribute to high blood pressure attenuation in hypertension secondary to AoCo.

Effect of clofibrate on vascular reactivity in a model of high blood pressure secondary to aortic coarctation.

The aims of this study were to identify the effect of clofibrate administration in the development of high blood pressure secondary to aortic coarctation (AoCo) and to assess its effect on vascular reactivity. Three experimental groups of rats were used: sham-operated, aortic coarctated vehicle-treated (AoCo-V), and aortic coarctated clofibrate-treated (AoCo-C100). The rats were treated for seven days. Blood pressure was measured, and the vascular response to angiotensin II (AngII), norepinephrine (NE), and acetylcholine (ACh) were evaluated in aortic rings. The activity and expression of endothelial nitric oxide synthase (eNOS) was also evaluated. The major findings of this study include the following: AoCo induced a rise in blood pressure, and this effect was attenuated by clofibrate. The vascular response to AngII was higher in aortic rings from the AoCo-V group compared to the Sham-V or AoCo-C100 groups. ACh-elicited vasorelaxation was lower in the arteries of AoCo-V rats than Sham-V or AoCo-C100, while it was comparable between the Sham-V and AoCo-C100 groups. In every case, vasorelaxation was dependent on NO. However, the ACh-induced release of NO as well as NOS activity and expression were reduced in the arteries of AoCo-V rats. Clofibrate maintained normal NOS activity and increased eNOS expression. In conclusion, clofibrate administration attenuated the AoCo-induced rise in blood pressure by a mechanism that involves the participation of the NO system at both the NO synthesis and the eNOS protein expression levels. These events improved endothelial function, preserved normal vascular responses to both vasorelaxants and vasoconstrictors, and led to better blood pressure control.